Ginsenoside Rg1 ameliorates lipopolysaccharide-induced depressive-like behaviors in mice by attenuating neuroinflammation and neuronal damage

Ginsenoside Rg1 (Rg1), a major active component of ginseng, exerts antidepressant-like effects, but the mechanisms underlying its anti-inflammatory activity and association with hippocampal neuronal remain unclear. A depression model was established in ICR mice via lipopolysaccharide (LPS) injection to investigate the effects of Rg1 on neuroinflammation and neuronal injury, as well as its antidepressant mechanism. Cognitive dysfunctions were evaluated via forced swim test (FST), sucrose preference test (SPT) and elevated plus maze (EPM). The effects of LPS-induced neuronal damage and Rg1 on anti-inflammatory pathways were subsequently evaluated through biochemical assays, and histological analysis, including Hematoxylin and Eosin staining, Nissl staining, Immunohistochemistry, ELISA and transmission electron microscopy (TEM). After confirming Rg1's antidepressant activity, its possible mechanisms were analyzed through Proteomic. Finally, Western blot was used to detect the key targets for predictive mechanisms. Results showed Rg1 significantly ameliorated LPS-induced depressive-like behaviors, reduced serum pro-inflammatory cytokines, attenuated neuronal loss, and increased hippocampal NeuN-positive cell density. The p-MST1/MST1 and p-YAP/YAP ratios were elevated in the model group but reversed by Rg1 and fluoxetine treatment. This study indicated Rg1 exerts antidepressant effect in mice, possibly by inhibiting hyperphosphorylation of key Hippo-YAP signaling pathway proteins.